© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 44-51,
2001
© 2001 Oxford University Press
Adjuvant Therapy for Very Young Women With Breast Cancer: Need for Tailored Treatments
Affiliations of authors: A. Goldhirsch, International Breast Cancer Study Group (IBCSG), Bern, Switzerland, European Institute of Oncology, Milan, Italy, and Oncology Institute of Southern Switzerland, Lugano, Switzerland; R. D. Gelber, IBCSG Statistical Center, and Dana-Farber Cancer Institute, Boston, MA; G. Yothers, National Surgical Adjuvant Breast and Bowel Project (NSABP) Biostatistical Center and Department of Statistics, University of Pittsburgh, Pittsburgh, PA; R. J. Gray, Eastern Cooperative Oncology Group Statistical Center, Boston, MA, and Dana-Farber Cancer Institute, Boston, MA; S. Green, Southwest Oncology Group Statistical Center and Fred Hutchinson Cancer Research Center, Seattle, WA; J. Bryant, NSABP Biostatistical Center and Departments of Statistics and Biostatistics, University of Pittsburgh, PA; S. Gelber, IBCSG Statistical Center, Boston, and Frontier Science and Technology Research Foundation, Brookline, MA; M. Castiglione-Gertsch, IBCSG Coordinating Center and University of Bern, Switzerland; A. S. Coates, University of Sydney and Australian Cancer Society, Sydney, Australia
Correspondence to: Aron Goldhirsch, M.D., International Breast Cancer Study Group, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy (e-mail: agoldhirsch{at}sakk.ch).
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ABSTRACT |
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 TopNotes Abstract Incidence and PrognosisEffects of Available Systemic...ConclusionsReferences |
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Breast cancer rarely occurs in women below the age of 35 years. Data from various sources indicate that diagnosis at such an age is associated with a dire prognosis mainly because of a more aggressive presentation. Although the effect of chemotherapy for premenopausal patients is substantial, recent evidence on 2233 patients suggested that very young women with endocrine-responsive tumors had a statistically significantly higher risk of relapse than older premenopausal patients with such tumors. In contrast, results for younger and older premenopausal patients were similar if their tumors were classified as endocrine nonresponsive. Information from studies on 7631 patients who were treated with chemotherapy alone in trials of three major U.S. cooperative groups showed a similar interaction between the effect of age and steroid hormone receptor status of the primary tumor. Better treatments for very young patients are required and may involve ovarian function suppression in addition to other endocrine agents in patients with endocrine responsive tumors and a more precise investigation of chemotherapy and its timing, duration, and intensity in those with endocrine nonresponsive tumors. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues, which further complicate the phase of treatment decision making. The development of more effective therapies for younger patients requires tailored treatment investigations and cannot rely on information predominantly contributed from older premenopausal women.
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INCIDENCE AND PROGNOSIS |
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TopNotesAbstractIncidence and PrognosisEffects of Available Systemic...ConclusionsReferences |
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Breast cancer rarely occurs in very young women. About 2% of the patients with the disease are less than 35 years old at diagnosis (1) Below the age of 20 years, the incidence is estimated to be 0.1 per 100 000 women, increasing to 1.4 for women 20–24 years old, 8.1 for women 25–29 years old, and 24.8 for women 30–34 years old (1) Breast cancer at a young age has a more aggressive biological behavior and is associated with a more unfavorable prognosis compared with the disease arising in older premenopausal patients. Specifically, tumors in younger women present with a higher grade and have a higher proliferating fraction and more vascular invasion than those occurring in older patients (2–5) Information from older series indicated that more positive axillary lymph nodes are detected in younger, compared with older, patients. Recent observations at the European Institute of Oncology, Milan, Italy, showed that the proportion of patients with lymph node-positive disease among 185 patients below 35 years of age was similar to that for 1242 patients 35–50 years old treated at the institute between April 1997 and August 2000. Changes in the attention paid to axillary lymph node involvement related to sentinel lymph node work-up might explain this finding. Results from the same, as yet unpublished, study also indicated that patients under 35 years of age had a higher grade and higher expression of Ki67, a higher percentage of vessel invasion, and less expression of estrogen receptor (ER) and progesterone receptor but similar overexpression of HER2/neu in the primary tumor.
Results from two population-based studies indicate that the risk of death is highest among the youngest and the oldest cohorts when compared with the patients of intermediate age (3), even when the analysis allows for differences in initial tumor stage (5) A review of the National Cancer Data Base (6) reveals that patients younger than 35 years of age have more advanced disease at diagnosis and a poorer 5-year survival than older premenopausal patients. Similar findings have been reported from the National Cancer Institute SEER1 database (7), from the Finnish Cancer Registry (8), from the Southwest Oncology Group (SWOG) database (9), and from a recent Danish study on young patients who did not receive adjuvant therapy (10, as well as from several series described from single centers (11–13)
Why Focus on Breast Cancer in Women Less Than 35 Years Old?
In addition to considerations related to presentation of disease and prognosis, women under 35 years of age with breast cancer face some specific problems that are less relevant for older premenopausal patients. It is clear, however, that trials reporting results for premenopausal women largely reflect outcomes for patients in their 40s. Table 1
indicates some of the issues that are specific for younger women. These issues include considerations of very late effects of radiation therapy; pregnancy after breast cancer; and interpersonal, family, and professional relations.
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Age and Chemotherapy-Induced Amenorrhea
Current adjuvant chemotherapy, which is extensively used across the board in premenopausal patients because of its overwhelming effects on outcome (14, is less likely to have definitive endocrine effect (suppression of endocrine ovarian function) in women younger than 35 years old. This is a major issue influencing the selection of adjuvant therapies for very young patients. Table 2 displays the incidence of chemotherapy-induced amenorrhea in 1054 patients treated with a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (classical CMF) for three to nine courses. No endocrine therapy was prescribed. All patients had lymph node-positive breast cancer (15)
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In this cohort, some of the patients who had amenorrhea subsequently resumed menses, so that only 8% of the younger patients, compared with 59% of the older patients, had permanent amenorrhea. Furthermore, the incidence of ovarian endocrine suppression is proportional to the duration of chemotherapy (16) It is known that chemotherapy exerts some of its effects in this age group via endocrine mechanisms (17).
Acceptance of ovarian function suppression is a significant problem for the younger patients (18,19). Facing objective and subjective symptoms of menopause, psychologic distress, and the potential need to adjust to changes in personal and family plans requires specific attention. Chemotherapy also seems easier to offer (in terms of acceptance) to the younger patients because of its shorter duration and the lesser degree of long-term effects on endocrine functions. These aspects require specific investigations focusing on the youngest cohorts.
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EFFECTS OF AVAILABLE SYSTEMIC TREATMENTS |
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TopNotesAbstractIncidence and PrognosisEffects of Available Systemic...ConclusionsReferences |
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Typically, young patients receive chemotherapy, and in many countries, clinicians have been reluctant to employ ovarian ablation or other endocrine treatment (10). The Danish Group studied patients enrolled in clinical trials between 1977 and 1996 with respect to age. During this period, they observed 867 patients (8.4%) who were less than 35 years old and 9489 patients who were 35–49 years old. Their analysis was based on the recommendations from the St. Gallen Conference (20), which indicated that an age less than 35 years is a dire prognostic variable. Patients with a lower risk of relapse (based on lymph node status, tumor size, and histologic grade but not hormone receptor status) were untreated with adjuvant systemic therapy, while the high-risk patients were offered participation in trials with chemotherapy or endocrine therapy or a combination of both (10). In this study, among patients who were predefined as having a low-risk disease and who, therefore, were given no adjuvant systemic treatment, the youngest cohort had a significantly increased risk of dying compared with older women. The increased risk with decreasing age at diagnosis (adjusted relative risk [RR] with the 45- to 49-year-old cohort as the reference group having an RR of 1.00) was 1.12 (95% confidence interval [CI] = 0.89 to 1.40) for the 40- to 44-year-old group, 1.40 (95% CI = 1.10 to 1.78) for the 35- to 39-year-old group, and 2.18 (95% CI = 1.64 to 2.89) for the under 35-year-old group. No such trend according to age was seen in patients who were considered to have high-risk disease and who were, therefore, eligible to receive adjuvant cytotoxic treatment. Thus, the negative prognostic effect of young age (<35 years old) compared with patients who were 45–49 years old was confined to those who were not offered a trial including adjuvant cytotoxic treatment. This lead to the conclusion that young women with breast cancer, on the basis of age alone, should be regarded as high-risk patients and should be given adjuvant cytotoxic treatment. This latter conclusion relies on the assumption that the worse prognosis predicts responsiveness to chemotherapy. Information on differences in treatment effects according to steroid hormone receptor status of the primary tumor was not reported in this analysis.
The International Breast Cancer Study Group (IBCSG) (formerly the Ludwig Breast Cancer Study Group) reported previously on 3700 premenopaual and perimenopausal patients who were included in IBCSG Trials I (21), II (22), V (23,24), and VI (15) conducted by the group between 1978 and 1993 (25). Of these women, 314 (8.5%) were less than 35 years old at study entry. Relapse and death occurred earlier and more often in younger (<35 years old) than in older (
35 years old) patients. The 10-year disease-free survival (DFS) for younger patients was 35% versus 47% for older patients (P<.001), and the 10-year overall survival (OS) was 49% versus 62% (P<.001), respectively. Younger patients with ER-positive tumors had a significantly worse prognosis than did younger patients with ER-negative tumors (10-year DFS was 25% for ER-positive tumors versus 47% for ER-negative tumors; P = .014). In contrast, among older patients, the prognosis was similar for patients with ER-positive tumors compared to patients with ER-negative tumors (10-year DFS was 45% versus 46%; P = .27). The interaction between age and ER status on outcome was statistically significant (P = .002). Of the 3098 patients with known ER status, 2233 (72%) received at least three courses of adjuvant chemotherapy alone. This retrospective analysis suggests that the endocrine effects of chemotherapy alone were insufficient for the younger patients with endocrine-responsive breast cancer.
Adjuvant Chemotherapy Alone and Outcome According to Age
To investigate further the hypothesis that there exists an interaction between age and ER status in premenopausal women treated with chemotherapy alone, the major U.S. cooperative groups were invited to conduct a similar analysis in their trial populations. The National Surgical Adjuvant Breast and Bowel Project (NSABP), the Eastern Cooperative Oncology Group (ECOG), and the SWOG provided information on outcome of patients assigned to receive chemotherapy alone within premenopausal age cohorts—premenopausal patients for ECOG and SWOG and patients aged 49 years and younger for NSABP. In addition, the IBCSG analysis was restricted to patients assigned to receive at least three courses of classical CMF, a duration similar to four courses of a doxorubicin (Adriamycin)–cyclophosphamide (AC) regimen, an adjuvant chemotherapy program frequently used in U.S. trials. All patients had a known ER status. From IBCSG trials, 2233 patients met these criteria (15,21–23). Included were 5849 patients 49 years of age or younger whose ER status was ascertained and who were randomly assigned to receive chemotherapy alone in NSABP trials that included both ER-positive and ER-negative cases [B-06 (26,27), B-09 (28), B-11 (29), B-15 (30), B-18 (31), B-22 (32), and B-25 (33)]. Also included were 1112 premenopausal patients assigned to receive chemotherapy alone in the ECOG trials EST5177 (34), EST5188 (35), and EST3189 (36) and 670 premenopausal patients assigned to receive chemotherapy alone in SWOG trial S8897 (37) for lymph node-negative disease.
Table 3 summarizes the results from all four cooperative groups. In each case, the RR of an event, estimated from a Cox proportional hazards regression model stratified by study and treatment group, is substantially higher for young patients with ER-positive tumors compared with the reference population of older patients with ER-positive tumors. In contrast, the difference in outcome with respect to age group is much smaller for patients with ER-negative tumors. The interaction between age and ER status was statistically significant for the cohorts in the IBCSG, NSABP, and SWOG trials. The bottom portion of Table 3 displays the 5-year DFS percentages calculated by applying the RR to the Kaplan–Meier estimates obtained for the reference population.
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Fig. 1
shows the Kaplan–Meier plots of DFS (IBCSG, SWOG) and relapse-free interval (NSABP) for ER-positive versus ER-negative cohorts separately for younger (<35 years old) and older (35 years old) premenopausal women enrolled in chemotherapy-only treament groups. Curves are not entirely appropriate for the ECOG dataset because of the confounding of treatment, lymph node status, and ER status in the different patient cohorts. The plots from the other three groups reveal a consistent pattern confirming a worse outcome for young patients with ER-positive tumors who are treated with chemotherapy alone. The nonproportionality of hazards for ER-positive and ER-negative cohorts is also evident, indicating that the RR in Table 3
should be interpreted as average hazards over the time interval.
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Endocrine Effects of Cytotoxic Adjuvant Therapy
Is failure to achieve chemotherapy-induced amenorrhea associated with an increased risk of relapse among premenopausal patients with ER-positive tumors? Table 4 shows the RR of relapse comparing patients with no amenorrhea versus those with amenorrhea treated with at least three cycles of classical CMF on IBCSG trials (25). A landmark analysis was used excluding patients who had relapsed or died within 9 months of randomization. Amenorrhea was defined as cessation of menses at each of the 3-, 6-, and 9-month follow-up visits for Trials I, II, and V or at the 9-month follow-up visit for women in Trial VI. Subgroups of patients defined by age and ER status are shown in Table 4. For both young and older premenopausal women with ER-positive tumors, no amenorrhea is associated with a higher risk of relapse, although the result in younger women is statistically uncertain because of the small sample size. The difference in the proportion of patients who achieve amenorrhea in the young age group might contribute to the poor outcome of these women with endocrine-responsive tumors treated with chemotherapy alone. In contrast, the association between failure to achieve chemotherapy-induced amenorrhea and risk of relapse is not statistically significant for patients with ER-negative primaries. Whether treatments that provide ovarian function suppression should be offered to women who continue to menstruate following adjuvant chemotherapy requires study in a randomized clinical trial.
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Various Adjuvant Approaches and Outcome According to Age
What evidence exists concerning differences in outcome according to age for premenopausal patients who receive other types of adjuvant therapies? Table 5 shows the RR of relapse between age groups less than 35 years and those 35 years old and older on the basis of data from the four cooperative groups. An RR greater than 1.00 indicates that the younger patients have a higher risk of relapse when compared with the older patient cohort. In addition to the NSABP trials that included the chemotherapy-only treatment groups presented in Table 3, Table 5 displays data from treatment groups allocated to no adjuvant therapy [from B-06 (26,27), B-13 (38), and B-14 (39)], treatment groups allocated to tamoxifen alone given for 5 years [from B-14 (39), B-16 (31), and B-20 (40)], and treatment groups allocated to chemotherapy plus tamoxifen [from B-09 (28), B-12 (29), B-20 (40), and B-23 (41)]. The ECOG data for the chemotherapy plus tamoxifen treatment group come from the cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, and tamoxifen (CMFPT) arm of EST5177 (34) and from all patients enrolled in EST5181 (42). The SWOG data for the chemotherapy plus tamoxifen treatment group come from the same S8897 study (37) that provided the data for the chemotherapy-alone group. ER-positive disease is shown in the upper part of Table 5, and ER-negative disease is shown in the lower part.
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The interaction with ER status described for the chemotherapy group is evident—RR of relapse for younger women compared with older women is higher for ER-positive cohorts compared with ER-negative cohorts. Differences in outcome according to age for no treatment and for chemotherapy plus tamoxifen are very similar, and interactions with ER status are not statistically significant. The large RR for tamoxifen given alone for 5 years for the ER-positive cohort is noteworthy: Younger premenopausal patients do worse than older premenopausal women when treated with tamoxifen alone. Whether tamoxifen alone improves outcome compared with no adjuvant treatment for both younger and older premenopausal women requires evaluation within the randomized studies. A priority research question is whether endocrine ovarian suppression, added to tamoxifen with or without chemotherapy, might improve outcome. Such a treatment approach has been demonstrated to be effective in a single trial in advanced breast cancer (43).
For the ER-negative cohort displayed in Table 5, the beneficial effects of chemotherapy might be similar for younger and older premenopausal women. In fact, in Trial B-13 (38), which is specifically designed for ER-negative disease, the effect of chemotherapy compared with no adjuvant treatment in women less than 50 years old is overwhelming, corresponding to a 38% reduction in the risk of relapse (Table 6). In this setting of ER-negative disease, the magnitude of the estimated effect of chemotherapy is the same for younger as for older patients although, because of the smaller sample size, the result for the younger group is statistically uncertain.
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F) versus no adjuvant therapy (nil)—results from National Surgical Adjuvant Breast and Bowel Project Trial B-13 for estrogen receptor-negative, lymph node-negative cases
Endocrine Nonresponsive Tumors
Regardless of the age of premenopausal patients with ER-negative tumors, adjuvant chemotherapy appears to be a very important component of a successful treatment regimen. It is hypothesized that questions relating to the direct cytotoxic effects of chemotherapy should be investigated specifically in patients with endocrine-nonresponsive tumors without the confounding effects of hormonal therapies or endocrine effects of chemotherapy. For example, timing of the start of chemotherapy after surgery; type, schedule, and duration of the cytotoxic regimen; and especially dose escalation and dose density of chemotherapy should be investigated in this patient population. ER-negative status is the typical criterion for defining endocrine nonresponsive tumors in clinical trials and in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview. A large number of markers (e.g., HER2/neu, p53, etc.) might prove to be useful in the future to refine the selection of chemotherapy for patients whose tumors are exclusively affected by cytotoxic agents (44).
Endocrine Responsive Tumors
We observed from several trials conducted during the past two decades that younger premenopausal patients treated with chemotherapy alone have a higher risk of relapse and death than older premenopausal women treated in the same way, especially if their tumors express hormone receptors. For young patients whose tumors express hormone receptors, endocrine effects of chemotherapy alone are modest, and endocrine therapies appear to be an essential component of an effective adjuvant therapy program. Whether use of "optimal" endocrine therapy (e.g., ovarian function suppression plus tamoxifen) may be sufficient for these patients is a hypothesis that has not been tested adequately. It must be recognized that factors influencing acceptance of endocrine therapies by very young women are complex, involving issues such as treatment duration (typically several years), induced menopausal symptoms, and issues of sexual functioning and family planning.
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CONCLUSIONS |
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TopNotesAbstractIncidence and PrognosisEffects of Available Systemic...ConclusionsReferences |
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A significant proportion of the youngest patients with breast cancer have a dire prognosis, in part, because of a more aggressive presentation of the disease. The belief that an increased risk of relapse justifies use of cytotoxic agents to increase cancer cell kill and the demonstration of significant chemotherapy efficacy for premenopausal women (most of whom are >34 years of age) contributed to lack of progress in evaluating endocrine therapies for this rare presentation of breast cancer. Furthermore, treatment decision making for very young women with newly diagnosed breast cancer may be affected by the strong emotional involvement of care providers.
There is an urgent need for tailored treatment investigations, especially in this younger population, for whom chemotherapy is prescribed across the board. Endocrine therapies, which are not easy to offer to very young patients, must be investigated in hormone-responsive disease because substantial evidence exists that current approaches are suboptimal. We must improve our understanding about how best to use endocrine approaches, including ovarian function suppression, use of selective estrogen receptor modulators (SERMs) and other endocrine agents, and possibly timing of surgery with respect to the phase in the menstrual cycle.
We might also consider reinvestigating questions related to chemotherapy in younger patients: Questions of timing, duration, and intensity of chemotherapy might be answered more precisely in patients with endocrine nonresponsive tumors, for whom endocrine effects of chemotherapy do not confound our observations.
Questions of endocrine therapies (tamoxifen or ovarian suppression or the combination of both) and of cytotoxic agents should also be considered with respect to the patient's desire to become pregnant and with respect to the presence of BRCA1 and BRCA2 mutations. These relatively rare conditions were not studied prospectively in the past, and a focused investigation might result in treatment indications, which cannot otherwise be extrapolated from trials on an older population.
Accrual of younger women to past and current clinical trials is insufficient to allow significant progress on treatment of these patients. Prospectively designed global collaboration to specifically investigate therapeutic approaches for young patients with breast cancer is required.
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NOTES |
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Supported in part by Public Health Service grants CA69651, CA23318, CA38926, CA37429, and CA75362 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research. 
We thank the patients, investigators, nurses, and data managers and all other members of the NSABP, ECOG, SWOG, and IBCSG for their cooperation. We particularly thank Gordon Bass for his help in preparing the NSABP's pooled dataset for the cross-protocol analysis, Danika Lew for her help with the data analyses from the SWOG trial, and Donna Levy for her help with the figure.
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